1. Field of the Invention
The present invention generally relates to chemical compounds and compositions that are useful as laser dyes and in photodynamic therapy.
2. General Discussion of the Background
A demand currently exists for chemical compounds having a high degree of stability and quantum fluorescence yield. These materials are usable for numerous purposes, including the generation of laser light. Substantial research has been conducted involving chemical laser systems capable of operating in the near UV/visible/near IR spectral regions. Dye lasers offer the greatest promise in meeting these requirements.
In the late 1960s, organic dye lasers tunable over a wide frequency range were developed. The light beams produced by these lasers were capable of being concentrated into an extremely narrow band through the use of diffraction gradient systems or other optical devices. Today, dye lasers are used for a variety of purposes in numerous technical fields including medicine and applied physics. For example, they may be used to conduct spectral analysis of chemical compounds. Also, they are useful in facilitating the analysis of photosynthetic and biomolecular reaction processes. Dye lasers in the medical field are used for numerous applications including cancer therapy, ophthalmological studies, surgeries and the like.
Typically, the lasing materials used in dye laser systems consist of fluorescent organic dye compounds dissolved in a liquid solvent. As discussed in Laurence, C. L., The Laser Book--A New Technology of Light, Prentice Hall Press, New York, 1986, one of the most important capabilities of dye lasers is their high degree of wavelength tunability. For example, the wavelength output of conventional dye lasers may be scanned over a 10-40 nm range. Through the use of different dye types, laser light output can be achieved at wavelengths from near ultraviolet to near infrared. Dye lasers are capable of being tuned because the chemical dyes which they use have specific vibrational and rotational energy levels which can be characterized.
Laser dye efficiency, laser action threshold, and flashlamp performance are closely inter-related. Desirable excitation from a large flashlamp with a slow rise-time requires (1) lower triplet-triplet (T--T) absorption of the laser dye over its fluorescence region .eta..sub.T (.lambda..sub.F), (2) shorter triplet state (phosphorescence) lifetime .tau..sub.p, and (3) laser dye quantum fluorescence yield close to unity (.THETA. near 1). (Drexhage in Dye Lasers, Springer Verlag, 1977.) Most of the commercially available and generally used dye molecules accumulate in their triplet state due to intersystem crossing when they are excited by a light source. Many commercially available laser dyes also unfortunately show T--T absorption in the spectral region of their laser action. Other problems with existing laser dyes include poor photostability and thermal stability, and relatively low solubility.
The selection of dyes for use in dye lasers is presently accomplished by trial and error. Numerous organic compounds showing strong fluorescence have been synthesized and are commercially available. However, very few of these materials are suitable for use in dye lasers. Most commercially used laser dyes primarily consist of coumarin and rhodamine compositions. These dyes, along with other commercially available materials, have only moderate energies and relatively high degrees of photodecomposition. In addition, many dyes require excitation using flashlamp systems with steep risetimes of 1 microsecond or less. Flashlamps meeting these requirements are difficult to construct for operation above 200 Joules.
Chelation of aluminum dichloride by a pyrromethene bidentate ligand has been reported to give an unstable orange solid; light absorption and emission data have not been reported for this compound. Treibs and Kreuzer, Liebigs Ann. Chem., 718:208, 1968; 721:116, 1969. Pyrromethene (P)-metal (M) chelates (P.sub.2 M) of tetracoordinate zinc, nickel, and copper have shown weak fluorescence above 500 nm (.THETA..about.10.sup.-3). Falk et al., Monatsh. Chem., 718:208, 1968; 721:116, 1969. However, fluorescence is not important for laser activity. Pyrazoboles (dimeric 1-borylpyrazole chelates of dialkylboron (BR.sub.2)) and the BF.sub.2 complexes of 1,2,3,4-tetrahydro-1,10-phenanthroline have not been found to be fluorescent. Trofimenko, J. Amer. Chem. Soc., 89:3165-3170, 1967; 92:5118, 1970; Klebe, et al., Chem. Ber. 116:3125, 1983.
Modest laser activity (.lambda..sub.las 420 nm) was reported for a "boratriazinium" salt by Basting et al., Appl. Phys., 3:81, 1974, however the structure was not established.
Another important use for fluorescent dye compositions involves the detection and treatment of diseased tissues using photodynamic therapy (PDT) techniques. These techniques, traditionally involving the administration of a photosensitizing drug to a patient, result in the distribution of a drug throughout the patient's body. The drugs or chemicals subsequently localize in areas of diseased tissue which is then illuminated with light of an appropriate wavelength to activate the drugs or chemicals. This photoactivation results in photochemical reactions in the diseased tissues that ultimately cause cytotoxic injury and/or death to the tissues.
There are currently two generally proposed mechanisms by which photosensitizing drugs are chemically altered upon illumination by an appropriate light source. The first mechanism (Type I) typically involves hydrogen atom abstraction from the drugs, thereby producing free radicals. Subsequent reactions of the radical products with other organic molecules or with oxygen results in biochemical destruction of the diseased tissue.
The other reaction mechanism (Type II) normally involves energy transfer from the electronically excited drugs to oxygen, producing singlet molecular oxygen which consequently reacts with a variety of substrates to produce oxygenated products. This pathway can also result in electron transfer from the excited drug to oxygen, producing an oxidized drug product in combination with superoxide ions. This reaction mechanism, along with the first mechanism described above, is schematically presented in the following formula: ##STR3##
Photodynamic therapy has been used experimentally in cancer patients since 1972. One experimental drug known as Photofrin II (a purified version of hematoporphyrin) has undergone randomized clinical trials in photodynamic therapy. Other photosensitizing drugs used in photodynamic therapy procedures include phyhalocyanines (merocyanine 540), substituted prupurines, xanthenes (Rhodamine 123 6G&B) cationic cyanine dyes, chlorine polymers, chalcogenapyrylium dyes containing selenium or tellurium atoms in the chromophore, phenothiazinium derivatives, benzophenoxoniums (Nile Blue A) and triarylmethanes (Victoria Blue BO [VB-BO]). The exact mechanisms used by the above chemicals to destroy diseased tissues (including cancer cells) upon exposure to an excitory light source is currently unknown. Moreover, the efficacy of these and other currently used chemicals in photodynamic therapy has not been entirely substantiated, although positive results have been demonstrated in many instances.
Ongoing research has involved a search for photochemicals of improved stability which express minimal side effects. A major side effect caused by currently used drugs is the development of uncontrolled photosensitivity reactions in patients after systemic drug administration. Upon exposure to the sun, patients develop generalized skin photosensitization. Ongoing research has specifically involved a search for chemicals which avoid these side reactions.
As described above, numerous chemicals have been synthesized which show strong fluorescence and potential value as photosensitizing drugs. "Fluorescence" as used herein is defined as a spontaneous random emission of light resulting from the transition of a molecule from the excited singlet state (S.sub.1) to the ground state (S.sub.0). Many photochemical reactions arise from the triplet state (T.sub.1). However, most photochemical drugs accumulate in a triplet state due to intersystem crossing. These triplet molecules consequently absorb light more or less efficiently, depending on the magnitude of their triplet state absorption and concentration.
Thus, a need exists for photosensitizing chemicals which are useful in photodynamic therapy characterized by reduced triplet-triplet (T--T) absorption upon the application of light from an external source. Moreover, a need exists for photosensitizing drugs which are easily activated and are photochemically stable. The present invention satisfies this need, as described below.
It is an object of the present invention to provide improved organic chemicals that are cytotoxic when illuminated.
It is another object of the invention to provide improved organic chemicals that are suitable for use as laser dyes.
It is another object of the invention to provide improved laser dyes that offer a high degree of photochemical stability.
It is another object of the invention to provide improved laser dyes that are readily dissolvable and easy to use.
It is another object of the invention to provide improved laser dyes that offer a high fluorescence quantum efficiency (Q.sub.F &gt;0.7).
It is another object of the invention to provide improved laser dyes with low triplet-triplet (T--T) absorption, thereby enabling the use of flashlamp pumping systems having slower risetimes.
It is another object of the invention to provide improved laser dyes which produce laser light having a higher intensity in comparison with the light beams produced using conventional dyes.
It is another object of the invention to provide an improved method for photodynamic therapy, particularly using chemicals which are stable, readily soluble and easily prepared.
An even further object of the invention is to provide an improved photodynamic therapy method using photosensitizing chemicals having reduced T--T absorption with a minimum overlap of fluorescence emission and that are cytotoxic.